ColVI myopathies: where do we stand, where do we go?

Abstract

Collagen VI myopathies, caused by mutations in the genes encoding collagen type VI (ColVI), represent a clinical continuum with Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) at each end of the spectrum, and less well-defined intermediate phenotypes in between. ColVI myopathies also share common features with other disorders associated with prominent muscle contractures, making differential diagnosis difficult. This group of disorders, under-recognized for a long time, has aroused much interest over the past decade, with important advances made in understanding its molecular pathogenesis. Indeed, numerous mutations have now been reported in the COL6A1, COL6A2 and COL6A3 genes, a large proportion of which are de novo and exert dominant-negative effects. Genotype-phenotype correlations have also started to emerge, which reflect the various pathogenic mechanisms at play in these disorders: dominant de novo exon splicing that enables the synthesis and secretion of mutant tetramers and homozygous nonsense mutations that lead to premature termination of translation and complete loss of function are associated with early-onset, severe phenotypes. In this review, we present the current state of diagnosis and research in the field of ColVI myopathies. The past decade has provided significant advances, with the identification of altered cellular functions in animal models of ColVI myopathies and in patient samples. In particular, mitochondrial dysfunction and a defect in the autophagic clearance system of skeletal muscle have recently been reported, thereby opening potential therapeutic avenues.

A Mouse Model for Dominant Collagen VI Disorders

“…Ullrich congenital muscular dystrophy (UCMD, OMIM #254090), the severe end of the clinical spectrum caused by an absence or marked deficiency of collagen VI, is currently recognized as one of the most common types of congenital muscular dystrophies (8 -11). Apart from muscle weakness, UCMD patients display connective tissue defects, including joint contractures, distal hyperlaxity, and skeletal anomalies (scoliosis, kyphosis, torticollis, spinal stiffness, and Achilles tendon contractures) (8,9). In addition, skin abnormalities, e.g.…”

“…resulting from dominant collagen VI mutations primarily, is at the mild end of the clinical spectrum (8,9). Due to a slowly progressive clinical course, more than two-thirds of the Bethlem myopathy patients over 50 years of age require aids for ambulation (14).…”

“…Due to a slowly progressive clinical course, more than two-thirds of the Bethlem myopathy patients over 50 years of age require aids for ambulation (14). Mutations in collagen VI also underlie disease phenotypes intermediate between classical UCMD and Bethlem myopathy, limb-girdle muscular dystrophy, and myosclerosis (OMIM #255600) (8,9,15,16). Mutations in the COL6A5 and COL6A6 genes have not been described to date.…”

“…The recessive UCMD patients typically bear homozygous or compound heterozygous nonsense or frameshift mutations, which trigger nonsense-mediated mRNA decay and thus result in complete absence or drastic reduction of collagen VI (8,9,19). Haploinsufficiency in collagen VI usually does not lead to a disease phenotype as almost all family members of the recessive UCMD patients who carry heterozygous mutations are healthy (17).…”

Sarcolemmal Specific Collagen VI Deficient Myopathy in a Labrador Retriever

“…The mouse model has led to significant discoveries in the pathogenesis of collagen VI‐related myopathies. More recently, zebrafish models of both UCMD and BM were created with morpholino antisense technology, and may be particularly useful for whole‐organism screens for pharmacologic treatments 15, 16…”